The use of porphyrin compounds in photodynamic therapy and related uses is well known, and numerous publications concerning various compositions useful in these applications have appeared. The development of the technology stems from the use of "hematoporphyrin derivative" (HPD) which is a complex mixture formed when hematoporphyrin dichloride is treated with a mixture of sulfuric and acetic acid according to the procedure of Lipson, R. L. et al., J Nat Cancer Inst (1961) 26:1-8. A substantial improvement in the efficacy of this type of drug was effected by Dougherty et al., U.S. Pat. No. 4,649,151, who showed that a fraction of HPD consisting of aggregates of 10 kd or greater was considerably more effective than HPD itself. This fraction, still a complex mixture, is commercially available under the trademark Photophrin.RTM. purified hematoporphyrin derivative.
The above-referenced U.S. Pat. No. 4,649,151 further describes in detail the method of phototherapeutic treatment using the fraction prepared. While treatment of tumors is exemplified, and it is known that the active compounds home to tumor tissue, it is clear that other therapeutic, diagnostic, and industrial applications of the photosensitizing ability of these materials are not excluded. More recent publications have specified particular alternative indications. For example, photosensitizing porphyrins are useful in the detection and treatment of atherosclerotic plaques, as described in U.S. Pat. Nos. 4,512,762 and 4,574,682. U.S. Pat. Nos. 4,500,507 and 4,485,806 describe the use of radiolabeled porphyrin compounds, including HPD, for tumor imaging. U.S. Pat. No. 4,753,958 to the University of California describes the use of topical application of porphyrin sensitizers for diagnosis and treatment of skin diseases. U.S. Pat. No. 4,748,120 describes the use of photosensitizers in the treatment of whole blood or blood components. Photochemical decontamination treatment of blood and components is also described in U.S. Pat. No. 4,727,027 where the photosensitizer is furocumarin and its derivatives. In addition, virus are inactivated in therapeutic protein compositions in vitro as disclosed in U.S. Pat. No. 4,268,947.
It is understood that the purified composition marketed as Photophrin.RTM. II purified hematoporphyrin derivative is a complex mixture. It is known that the mixture contains porphyrins joined by ether linkages (Dougherty, T. J. et al, Adv Exp Med Biol (1983) 160:3-13) and Kessel, D. et al., Photochem Photobiol (1987) 36:463-568 has shown that ester-linked porphyrins are contained in this mixture. Scourides, P. A. et al., Cancer Res (1987) 47:3439-3445 synthesized a mixture of oligomers of ether-linked porphyrins starting from hematoporphyrin dimethyl esters, which was active in assays for photodynamic treatment of tumors, but was as complex a mixture as the Photophrin.RTM. II preparation. Dimers of hematoporphyrin joined by ester linkages have also been prepared by Pandey, R. K. et al., Cancer Res (in press) and these dimers were shown to be absent from the mixture in the Photophrin.RTM. II composition, as well as active in an in vitro assay.
Thus, while it is known that complex mixtures of porphyrin derivatives obtained in a prescribed manner are useful and effective in various applications where photosensitizing activity is desirable, individual purified components which are responsible for the activity of the complex mixture have not been prepared and identified. It has now been found that the ether-linked monovinyl and divinyl dimers of porphyrin nuclei are active and effective in these applications. A summary of this discovery was published by the inventors herein in Tetrahedron Letters (1988) 29:2501-2504, which was mailed to subscribers on May 17, 1988. The disclosure of this paper is incorporated herein by reference.